Hughes, who had no formal training in art,[8] began his career in 1987.[4][11] His first comic book work was a pinup in Eagle #6. He penciled two short stories and the first issue of Death Hawk, created by Mark Ellis. In 1988 Hughes became the penciller on writer Mike W. Barr's detective series Maze Agency, as his portfolio bore samples of both that series and Mike Gustovich's Justice Machine. Maze Agency, published by Comico, and edited by Michael Eury, became Hughes' first regular series and his first color work. Despite wanting to draw action-oriented superhero stories at the time, he credits his work on Maze Agency, whose scripts Barr composed in the full script format, with improving his skill and confidence at storytelling. In a 2004 interview, he stated that this work also developed his preference for character-oriented stories over action-oriented ones, both as an artist and a writer. Hughes' interior pencils were inked by Eury's longtime friend Rick Magyar, and because Hughes aspired to ink his own work one day, he took Barr's suggestion that he produce pinups on each issue's back cover as an advertisement for the next issue to practice inking his own pencils. It was around this time that Hughes switched to inking with a brush on the advice of Dave Stevens when Stevens looked at Hughes' samples.[12] Hughes stayed on the series for a year.[13]

After two years of providing background art or interior pencils on independent books, writer/artist Bill Willingham, who like Hughes, had done work for Comico, introduced Hughes to Andy Helfer, the editor on the DC Comics series Justice League America. Helfer was impressed by Hughes' portfolio and asked Hughes to contact him when his contract expired. A few months later, after Comico went out of business, Helfer contacted Hughes, hiring him initially to draw inventory covers for issues like Mister Miracle #19, one of Hughes' favorite creations by Jack Kirby. Hughes was then made the regular artist on Justice League America, with issue #31 being his first published DC Comics work.[6][14] At the time he began on that book, he was still working at a comics shop two days a week.[15] He continued doing covers and interior art on the title for two years, before switching to providing covers only.

At the age of 24, Hughes moved to Atlanta, Georgia to join Gaijin Studios, believing that working more closely alongside fellow artists would improve his own skills. Hughes stayed with Gaijin Studios for 12 years.[10] That same year, he penciled Comics' Greatest World: Arcadia #3 for Dark Horse Comics, which featured the first appearance of the supernatural character Ghost. He drew that character subsequently in the 1994 one-shot Ghost Special. When that character was given her own series in 1995, Hughes penciled the first three-issue storyline, "Arcadia Nocturne".[13]

From 1994 to 1995, Hughes drew the satirical storyline "Young Captain Adventure", which appeared in the first several issues of the adult comics anthology magazine Penthouse Comix. Hughes also provided a painted cover for issue #2, and a pinup in issue #26 in 1997.[13] In a 2011 interview, he indicated that while he did not regret that work, he felt shame at the time he produced it, as he feared it might end his future prospects with companies like Marvel Comics and DC Comics, and because he feels that depicting full nudity is less fulfilling than merely suggestive art. Hughes explains:[16]

I firmly believe that drawing a fully clothed, beautiful woman is more sensuous than a completely naked, laying on a table getting ready to go in for a CAT scan. I firmly think that it's what you hint and suggest- that is more attractive- and that goes for both men and women. When you go into full nudity, and swing for the fences with the nudity, it can be titillating at first, but after a while you get kind of tired and kind of spent and decide 'Hey, you know what, I am just going to go watch the ball game.' I think that you need to have the mystery, and that layer to be peeled away so that the interest remains there.[16]

In 1995 Hughes wrote and illustrated the 1996 two-issue miniseries, Gen¹³: Ordinary Heroes from WildStorm, his first writing assignment. Because he did that at the WildStorm offices in La Jolla, California, he spent evenings in the suite where the studio's books were colored, where he learned how to color with Photoshop from colorists Homer Reyes, Ben Dimagmaliw and Laura Martin.[17]

In late 1998 he began a four-year run as cover artist on DC's Wonder Woman, producing 49 covers for the series. He also provided cover art on Tomb Raider from Top Cow Comics. He would eventually gain a reputation as one of the best known and distinctive comic book cover artists.[3]

When Wizards of the Coast created their 2000 d20-based Star Wars RPG, Hughes created designs for both the original and revised core rulebooks, as well as the Star Wars: Invasion of Theed adventure game mini-RPG. When he reused his portrait of the Jedi guardian, Sia-Lan Wezz (his favorite character), for the cover of the 2005 one-shot Star Wars: Purge as a gag, there was such editorial interest that she was written into the story as one of Darth Vader's early victims.[18]

In May 2007, a month after the release of the feature film Spider-Man 3, Sideshow Collectibles debuted a miniature statuette of Mary Jane Watson, a perennial love interest of Spider-Man's, based on artwork by Hughes. The statue, which depicts Mary Jane wearing a cleavage-revealing T-shirt and low-cut jeans that expose the top of a pink thong while bending over a metal tub holding Spider-Man's costume, generated controversy among some fans who felt that the statue was sexist.[19][20] Marvel addressed the matter by stating, "The Mary Jane statuette is the latest release in a limited edition collectibles line. The item is aimed at adults that have been long-time fans of the Marvel Universe. It is intended only for mature collectors and sold in specialty, trend, collectible and comic shops – not mass retail." Sideshow Collectibles stated, "Our product is not produced to make a political or social statement but is fashioned after entertainment properties currently in the market place (sic). We suggest that if you do find the Mary Jane product offensive that you refrain from viewing that web page." Elizabeth McDonald of girl-wonder.org, an organization dedicated to "high-quality character depiction" in the comics industry, was incredulous at the statue's design, though she stated, "Honestly, the difficulty with this statuette is that if you're a woman who likes comics, it's not even noteworthy. Many male comic fans can't understand the outrage it's generated, since this is fairly tame within the industry. This portrayal of Mary Jane could be considered superior to some in the industry, since her clothes don't seem to be actively falling off her". The Toronto Star's Malene Arpe echoed this, pointing to female characters with even more revealing appearances, such as Black Cat and Witchblade.[21][22] Gary Susman of Entertainment Weekly lamented that the statuette was not issued some weeks earlier, so that it could have been included in the website 10 Zen Monkeys' list of "Ten Worst Spiderman Tie-Ins".[23][24][25]

In 2008 DC Comics hired Hughes to create a poster of the major female characters in the DC Universe as a giveaway for that year's San Diego Comic-Con, to promote DC's upcoming projects. The poster, called "Real Power of the DC Universe", features 11 female characters, standing and sitting abreast of one another, as in a Vanity Fair gatefold layout. The characters are mostly clad in white outfits rather than their familiar superhero costumes, as per DC's request, so Hughes, wanting to avoid making the poster look like a bridal magazine layout, gave each outfit a slightly different color temperature. He also gave each character a distinctive style. The garment worn by Wonder Woman, for example, resembles a Greek stola, while the one worn by Poison Ivy features a floral trim. Because the Catwoman series was coming to an end, DC instructed Hughes to leave her off the poster, but Hughes, who was fond of the character, drew her on the far left, figuring that he would Photoshop her out of the final art. At the last minute, however, DC, having seen his progress, decided that liked her inclusion, and told Hughes to leave her in. She is dressed in a black latex evening gown, with only a white shawl, because Hughes had less than 24 hours after DC revised their decision to include her, and found it easier to render her in a black outfit. Hughes reasoned that Selina would be irritated at being intentionally left out and then being included as the last minute, and wore the blackest thing she could out of spite. The poster has become an iconic one, with a long-lived popularity, and has resulted in requests for Hughes to do various other similar ones with men, Marvel characters, etc. It is one of the images for which Hughes has gained a reputation as one of comics' foremost cheesecake artists.[1][2] About this status, Hughes has said:

I don’t know if I embrace the term 'cheesecake artist'. I don't like hugging anything. Maybe I give the term a warm yet firm handshake? It's great to be known for being good for something, and it not being altogether infamous.[1]

For an article by Hal Niedzviecki on the impact of blogs, social networks and reality television in the February 2009 Playboy magazine, Hughes illustrated a double-page spread depicting a group of voyeurs observing a topless woman in front of a computer.[26]

Although Hughes was announced as the writer and artist on All Star Wonder Woman in 2006,[27][28] he explained at the 2010 San Diego Comic-Con International that that project was "in the freezer" for the time being, due to the difficulty involved in both writing and illustrating it himself.[29] His website indicated that after the current Catwoman series ended with issue #82, he would cease his DC cover work, and would focus on producing the six-issue All Star Wonder Woman series,[30] though he stated in an October 2010 interview with NJ.com, after the Catwoman assignment had concluded earlier that year, that All Star Wonder Woman was still on hold.[8] At the 2010 Chicago Comicon, editor Mark Chiarello offered him the art duties on the four-issue miniseries Before Watchmen: Dr. Manhattan, one of eight tie-in prequels to the seminal 1986-1987 miniseries Watchmen, which would be written by J. Michael Straczynski, and which would require Hughes to delay finishing All-Star Wonder Woman. Hughes accepted the job of drawing that miniseries, which was announced in February 2012,[31][32][33] and premiered August 22, 2012.[34][35] Hughes commented: "I love Alan Moore's canon of work, with special affection for Miracleman, The League of Extraordinary Gentlemen, and most definitely Watchmen. I hope to do some sort of justice to Dave Gibbons' brilliant art: he's one of the all time great illustrators ever to work in the field of comics...I'm fairly stoked to be working with the fabulous J. Michael Straczynski [sic] I loved his Thor run, especially. The man knows how to craft amazing tales, so I feel like you & I are in good hands."[36]

In 2014 "She Lies at Midnite", an eight-page Batman/Catwoman story written and illustrated by Hughes using greytones, appeared in the sixth and final issue of the anthology miniseries Batman: Black and White.[37][38]

On July 20, 2016 Archie Comics published the first issue of Betty and Veronica, a series written and illustrated by Hughes. In the series, Betty Cooper and Veronica Lodge, who are both best friends and bitter rivals in the Archie books, will find themselves at odds over the fate of the town's hangout, Pop's Chocklit Shoppe, with the entire town divided on the matter. Hughes' intention is to make the characters timely and relevant, and although Hughes has stated that he favors Betty, he has also said that "Veronica Lodge is delicious good fun to write."[39]

On December 20, 2017 Dark Horse Comics published the 36-page Christmas special one-shot Hellboy: Krampusnacht, written by Hellboy creator Mike Mignola, and illustrated by Hughes.[40][41] Although Hughes had previously done a Hellboy pinup in a Dark Horse anniversary comic, Krampusnacht marks Hughes' first time doing the interiors on a Hellboy story, and his first collaboration with Mignola.[41] The book received mostly positive reviews.[42]

According to Hughes, he does not illustrate comics interiors on a regular basis because creating artwork whose quality satisfies him takes too much time for him to produce it on a regular monthly schedule, and that while he is capable of working faster, he is typically dissatisfied with the results when he does so.[44] As an example, he points to the 1996 miniseries he wrote and illustrated, Gen¹³: Ordinary Heroes, which took him ten months to complete.[11][45] He elaborated on this in a 2004 interview, explaining:

Storytelling is a lot of work, and to be a good storyteller is a lot of work because you have to pay attention to it. I think anybody with enough time under their belt can hack out a story. I think anybody can tell a safe story, or tell a story safely. You know, six panels, one head shot per page, that kind of thing. But to do it with any sort of style or creativity requires you to be on the ball all day long, and it's hard work. Whatever niche I occupy in comics right now, it's the goldfish filling the bowl that it's in. I can't do good storytelling and do it in a timely fashion, which is why nobody offers me stories any more. Any artist who does put out regular comics with interior stuff is a better man than me.[12]

Hughes varies his style between projects, sometimes exhibiting a "cartoony" look in his drawings, and at other times employing reference to achieve a photorealistic work in his art, as in his work for Playboy magazine, in order to produce more varied works for his portfolio, should his prospects in the comic book industry ever fade.[10]

The penciling process Hughes employs for his cover work is the same he uses when doing sketches for fans at conventions, with the main difference being that he does cover work in his sketchbook, before transferring the drawing to virgin art board with a lightbox,[46][47] whereas he does convention drawings on 11 x 14 Strathmore bristol, as he prefers penciling on the rougher, vellum surface rather than smooth paper, though he does enjoy brush inking on smoother paper,[48] and also illustrated some of his Catwoman covers on animation paper.[49] He does preliminary undersketches with a lead holder,[50] because he feels regular pencils get worn down to the nub too quickly. As he explained during a sketch demonstration at a comic book convention, during this process he uses a Sanford Turquoise 4B lead, a soft lead, though when working at home in Atlanta, where the humid weather tends to dampen the paper, he sometimes uses a B lead or 2B lead, which acts like a 4B in that environment.[48] However, his website explains that he uses 6B lead, with some variation. For pieces rendered entirely in pencil, he employs a variety of pencil leads of varying degrees of hardness.[43] After darkening in the construction lines that he wishes to keep, he erases the lighter ones with a kneaded eraser before rendering greater detail.[50] For more detailed erasures, he uses a pencil-shaped white eraser, and to erase large areas, he uses a larger, hand-held white eraser, which he calls a "thermonuclear eraser", because it "takes care of everything".[48]

For inking, which is Hughes' least favorite part of the illustration process,[51] he uses a size three Scharff brush and Dr. Ph. Martin's Black Star Hi-Carb ink.[43] Hughes also favors Faber-Castell PITT artist pens, which come in a variety of points, including fine, medium, bold and brush tips, which Hughes uses for brush work on convention sketches. Though he stated in a 2006 interview that he favored PITT pens for convention sketches, but never for cover work,[48] he later used them to illustrate the cover of ImagineFX magazine #67 in 2011,[47] and for an illustration of Fire and Ice for a Justice League card game.[52] He occasionally will use Copic markers in both warm and cool gray tones to render covers in gray scale.[43] In a similar manner to his penciling, Hughes tends to ink different portions of the sketch at random,[53] though when rendering an attractive female, he begins with the face, so that in the event that he fails to capture her good looks, an entire rendered illustration has not been wasted.[47] He uses Sharpie markers to fill in larger areas,[48] which he feels would be too tedious to render in pencil, such as the costumes of characters like Batman, which he believes should be rendered in black rather than blue.[46] He uses Photoshop to color his cover work.[8][43] He initially colored his covers after inking them traditionally, but beginning with Wonder Woman (Vol 2) #195, he switched methods to one in which he renders the greyscale stage in pencil, pen and marker like a painting, and then using Photoshop's Layer tool to colorize each element in the image separately.[54]

Hughes sometimes uses colored markers to embellish parts of a convention sketch, as when he uses red for female characters' lips, or a silver pen to render scenes set in outer space.[48][55] When rendering an entire sketch in grey tones or full color, Hughes, who once used Prismacolor or Design 2 markers, explained at the 2010 San Diego Comic-Con International that for the past four years, he had been using Copic markers, a set of which a fan gave him as a gift, because Copic markers are refillable, and because he found that they produce longer-lasting colors, and can be used several times longer than other brands,[56][57] as he was still using the same package of nibs as of August 2010 that came with the first set of Copics he was given four years previously.[58] When using Copics, he takes care to erase his pencils, and to not work dark-to-light, because of the mottled effects that result from doing so.[59] He has conducted demonstrations of Copic markers at conventions on a number of occasions.[60]